An important genetic risk factor for the development of alcoholism is differential sensitivity to an acute dose of alcohol. Acute alcohol responses are a function of the combined effects of initial sensitivity and acute functional tolerance (AFT), both of which are influenced by genetic factors. Using inbred mouse strains, we have been using a paradigm known as rapid tolerance - tolerance that develops within 24 hrs following a single exposure to alcohol - as a tool to investigate the genetics of acute alcohol responses. We have found that the Inbred Long and Short Sleep mouse strains (ILS and ISS) differ considerably in their ability to develop rapid tolerance using the loss of righting reflex test (LORR) as the measure of sensitivity. This strain- dependent difference appears to be mediated at least partly by differential effects on AFT. We hypothesize that genetic variance in rapid tolerance occurs as a result of genotype-dependent differences in baseline gene expression and in alcohol-mediated effects on gene expression. Thus, we propose to exploit the rapid tolerance model to examine the molecular and genetic basis of acute responses using a genetical genomics approach, an emergent area of research that combines linkage analysis with high- throughput gene expression technologies. The genetics of rapid tolerance, initial sensitivity, and AFT, and of the postulated gene expression events that contribute to genetic variance for the behavioral responses will be investigated using the LXS recombinant inbred (RI) mouse strain panel which was derived from the ILS and ISS. Expression profiling will be conducted with Affymetrix Mouse Exon microarrays with which it is possible to investigate effects on alternative splicing as well as on transcript abundance. The following five Specific Aims are being proposed to test the hypothesis: 1) determine relationships between initial sensitivity, AFT, and rapid tolerance for the LORR response in the LXS RIs; 2) map quantitative trait loci (QTL) for the responses determined in Aim 1; 3) conduct expression profiling in the cerebellum and striatum of the LXS RIs to identify genes whose expression co-segregates with the behavioral responses; 4) map expression QTL for genes identified in Aim 3 and for genes that occur within QTL intervals determined in Aim 2; and 5) confirm expression results for genes identified in Aims 3 and 4. We propose that the results of these experiments will offer insight into the nature of genetic variance for acute alcohol sensitivity. This in turn will contribute to a deeper understanding of genetic risk for human alcoholism.